A Microfluidic System Coupling Amplified Nanofluidic Virion Purification and Mass Spectrometry for Detection of SARS-CoV-2 There is an urgent need for new methods and alternative techniques for viral detection in response to the SARS- CoV-2 pandemic. A novel strategy is proposed for viral detection that purifies the virions with a nanofluidic/microfluidic (NF/MF) system prior to protein analysis by mass spectrometry. The NF/MF purification system and protein analysis are highly complementary to and a radical departure from existing approaches. The NF/MF system addresses the fundamental challenge of rapid and efficient purification of virions from the huge background of human cells and biomolecules. This novel approach will enable mining of the rich information that is contained in the protein structures of the virus. In contrast with most other approaches, this technology will be capable of detecting mutated strains of SARS-CoV-2 and emergent viruses. The performance of the novel NF/MF will be fully characterized for different clinical needs. First, the extraction efficiency of the NF/MF system and the limits of detection for the complete diagnostic system will be measured. Second, application specific data acquisition and analysis strategies will be developed for the MS that are tuned to: 1) achieve the best detection limits for diagnostic testing, and 2) to gain the greatest percentage of the viral proteome for enhanced diagnostics for patients with high-viral loads. In addition to the gains in capabilities, it is expected that performance, costs, and sample throughput will be favorable. It is anticipated that limits of detection of 10 virions or better will be achieved with sample throughput of a few thousand samples per day per system. The simplicity of the process and ease of automation will reduce personnel costs. Only a few consumables will be used that are orthogonal to the supply chain for RNA based methods. Thus, this technique is highly complementary to RNA-based approaches and would reduce vulnerability to supply chain disruption. It is anticipated that these figures of merit and the potential applications for utilizing the structural information contained in the proteins has the potential to revolutionize viral diagnostics in both short-term and long-term.